Acute kidney injury (AKI) is one of the most prevalent complications among hospitalized coronavirus disease 2019 (COVID-19) patients. Here, we aim to investigate the causes, risk factors, and outcomes of AKI in COVID-19 patients. We found that angiotensin-converting enzyme II (ACE2) and transmembrane protease serine 2 (TMPRSS2) were mainly expressed by different cell types in the human kidney. However, in autopsy kidney samples, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleoprotein was detected in ACE2+ or TMPRSS2+ renal tubular cells, whereas the RNAscope® Assay targeting the SARS-CoV-2 Spike gene was positive mainly in the distal tubular cells and seldom in the proximal tubular cells. In addition, the TMPRSS2 and kidney injury marker protein levels were significantly higher in the SARS-CoV-2-infected renal distal tubular cells, indicating that SARS-CoV-2-mediated AKI mainly occurred in the renal distal tubular cells. Subsequently, a cohort analysis of 722 patients with COVID-19 demonstrated that AKI was significantly related to more serious disease stages and poor prognosis of COVID-19 patients. The progressive increase of blood urea nitrogen (BUN) level during the course of COVID-19 suggests that the patient’s condition is aggravated. These results will greatly increase the current understanding of SARS-CoV-2 infection.
Background/Aims: To investigate the role of angiopoietin-2 (Ang-2) and IL-18 in the pathogenesis of diabetic nephropathy (DN) and the molecular mechanisms through which alprostadil protects renal function. Methods: DN was induced by streptozotocin and intraperitoneal injection of alprostadil was given to diabetic mice. After 2, 4 and 8 weeks of alprostadil treatment, the mRNA and protein expression of kidney Ang-2 and IL-18 were detected by reverse transcription PCR, Western blot and immunohistochemistry analyses. Mouse glomerular endothelial cells (GEnCs) were cultured in high glucose and treated with alprostadil. After transfection with an Ang-2-pcDNA and Ang-2-siRNA, both Ang-2 and IL-18 expression were measured by Western blot analyses. Results: Alprostadil treatment caused a significant decrease in the renal damage parameters. Both Ang-2 and IL-18 were significantly increased in DN mice and in GEnCs cultured in high glucose; however, their expression was greatly reduced by alprostadil treatment. Ang-2 could also increase IL-18 expression in cultured endothelial cells under high glucose, and this response was partially blocked by Ang-2 siRNA. Conclusions: Ang-2 and IL-18 may be associated with the development and progression of DN in mice. Alprostadil treatment can protect renal function by reducing proteinuria. These effects are mediated, at least in part, through down-regulation of Ang-2 and IL-18 expression.
Aims. To evaluate the levels of angiopoietin-1 (Ang-1), Ang-2, and vascular endothelial growth factor (VEGF) in serum and urine, and their association with albuminuria in patients with type 2 diabetes mellitus. Methods. In 113 type 2 diabetic patients with normoalbuminuria, microalbuminuria, and macroalbuminuria and 30 healthy controls, the levels of Ang-1, Ang-2, and VEGF in serum and urine were measured by enzyme-linked immunosorbent assay (ELISA). Results. Urinary and serum levels of Ang-2 were significantly higher in diabetic patients with normoalbuminuria than in healthy controls. Increased urinary Ang-2 level was positively associated with the degree of albuminuria. Urinary Ang-1 levels were significantly higher in normoalbuminuria patients and lower in macroalbuminuria patients than in controls. The levels of urinary VEGF increased in the albuminuria subgroup, though serum levels of Ang-1 and VEGF did not change. Urinary Ang-2 levels were correlated positively with albuminuria and negatively with glomerular filtration rate (GFR). Stepwise multiple regression analysis identified albuminuria (P < 0.001) and GFR (P = 0.001) as significant predictors of urinary Ang-2. Conclusions. Our data suggest that urinary Ang-2 is stepwise increased with renal damage in patients with type 2 diabetes mellitus and is associated with albuminuria.
Angiopoietins (Angs) are a family of vascular growth factors that share multiple cellular functions related to cell survival, proliferation, and migration. Angs play physiological and pathological roles through the Tie tyrosine kinase receptors. The Ang‐Tie signaling pathway participates in the developmental and tumor‐induced angiogenesis and is also involved in many disease settings, such as vascular diseases, systemic inflammation, and cancers. Since Angs are widely expressed in the kidney, an enormous amount of research focuses on their roles in the kidney. In this review, we describe the biological functions of the Ang‐Tie signaling pathway and summarize their roles in kidney development and maturation, acute and chronic kidney diseases, diabetic nephropathy, lupus nephropathy, hemolytic uremic syndrome, end‐stage renal diseases, and renal cell carcinoma. Understanding the molecular mechanisms of Ang‐Tie signaling may reveal potential therapeutic targets for preventing or alleviating kidney diseases.
The efficacy and safety of tacrolimus (TAC) and cyclophosphamide (CTX) in the treatment of idiopathic membranous nephropathy (IMN) were compared in Chinese adult patients using a meta- analysis of the available literatures. Randomized controlled clinical trials (RCTs) of the treatment of primary IMN with TAC or CTX combined with corticosteroids in the English databases PubMed, Embase and Cochrane, as well as Chinese databases, were searched. Qualified studies were subjected to quality assessment and meta-analysis. A total of 8 RCTs, including 359 Chinese patients, were included in the meta-analysis. The complete remission rate and overall remission rate in the TAC treatment group after 6 months of treatment were higher than those in the CTX treatment group. No significant difference in remission rate was found after 12 months of treatment. There was no significant difference in the adverse reaction between the two groups at the 6th or 12th months. TAC-based treatment was associated with a faster response than CTX at the 6th month, but there was no significant difference between the two groups at 12th month in Chinese adults. Further study is needed to evaluate the long-term efficacy and safety of this treatment regimen.
Renal aging has attracted increasing attention in today’s aging society, as elderly people with advanced age are more susceptible to various kidney disorders such as acute kidney injury (AKI) and chronic kidney disease (CKD). There is no clear-cut universal mechanism for identifying age-related kidney diseases, and therefore, they pose a considerable medical and public health challenge. Epigenetics refers to the study of heritable modifications in the regulation of gene expression that do not require changes in the underlying genomic DNA sequence. A variety of epigenetic modifiers such as histone deacetylases (HDAC) inhibitors and DNA methyltransferase (DNMT) inhibitors have been proposed as potential biomarkers and therapeutic targets in numerous fields including cardiovascular diseases, immune system disease, nervous system diseases, and neoplasms. Accumulating evidence in recent years indicates that epigenetic modifications have been implicated in renal aging. However, no previous systematic review has been performed to systematically generalize the relationship between epigenetics and age-related kidney diseases. In this review, we aim to summarize the recent advances in epigenetic mechanisms of age-related kidney diseases as well as discuss the application of epigenetic modifiers as potential biomarkers and therapeutic targets in the field of age-related kidney diseases. In summary, the main types of epigenetic processes including DNA methylation, histone modifications, non-coding RNA (ncRNA) modulation have all been implicated in the progression of age-related kidney diseases, and therapeutic targeting of these processes will yield novel therapeutic strategies for the prevention and/or treatment of age-related kidney diseases.
Transcytosis is an important intracellular transport process by which multicellular organisms selectively move cargoes from apical to basolateral membranes without disrupting cellular homeostasis. In kidney, macromolecular components in the serum, such as albumin, low-density lipoprotein and immunoglobulins, pass through the glomerular filtration barrier (GFB) and proximal tubular cells (PTCs) by transcytosis. Protein transcytosis plays a vital role in the pathology of albuminuria, which causes progressive destruction of the GFB structure and function. However, the pathophysiological consequences of protein transcytosis in the kidney remain largely unknown. This article summarizes recent researches on the regulation of albumin transcytosis across the GFB and PTCs in both physiological and pathological conditions. Understanding the mechanism of albumin transcytosis may reveal potential therapeutic targets for prevention or alleviation of the pathological consequences of albuminuria.
Alport syndrome (AS) is a rare and inherited renal disorder with an autosomal recessive mode of inheritance. AS patients usually manifest with hematuria and progressive renal disorder also occasionally accompanied by hearing loss and ophthalmic disease. Germline variants in collagen type IV α-4 (COL4A4) gene lead to autosomal recessive Alport syndrome. In the present study, we investigated a Chinese family with Alport syndrome. The index patient is a 24-year-old Chinese woman who has been suffering from proteinuria. Renal biopsy and renal pathology were performed and found focal segmental glomerulosclerosis (FSGS) like lesion in the index patient. The index patient also presented with binocular edema and blurred vision. However, binocular edema dissipated gradually without any further treatment. Unlikely, the index patient was not diagnosed with hearing impairment. Index patient’s parents are phenotypically normal. Targeted next generation sequencing and Sanger sequencing was performed. A novel heterozygous single nucleotide insertion, c.4760_4761insC and a previously reported likely pathogenic variant, c.1323_1340delTGGCTTGCCTGGAGCACC in the COL4A4 gene were identified in the index patient. The novel heterozygous single nucleotide insertion (c.4760_4761insC) leads to a frameshift which eventually results in the formations of a truncated COL4A4 protein. In addition, the other heterozygous likely pathogenic variant, c.1323_1340delTGGCTTGCCTGGAGCACC, has been already identified with causing AS an autosomal recessive mode of inheritance. Sanger sequencing confirmed that these two variants were inherited in the index patient from her father and mother, respectively. These two variants were not found in 100 normal control individuals. In conclusion, our present finding emphasizes the significance of high throughput targeted next generation sequencing technology for rapid and cost-effective genetic screening which allows us easy and accurate clinical diagnosis of AS patients.
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